Patient with congenital factor VII deficiency undergoing brain tumor neurosurgery successfully treated with recombinant factor VIIa and fresh frozen plasma: A case report and literature review

Rationale: Congenital factor VII deficiency is the most common among rare bleeding disorders, characterized by spontaneous or traumatic bleeding. The clinical manifestation is heterogeneous, ranging from asymptomatic phenotype to life-threatening hemorrhages. Intracranial hemorrhage is a common complication of brain tumor neurosurgery, which significantly challenges the perioperative management of patients with hemostatic defects. Patient concerns: This report presented a 55-year-old man with congenital factor VII deficiency, who had no history of hemorrhage or family history. He underwent a craniotomy for the treatment of papillary craniopharyngioma. Diagnoses: The patient was diagnosed as papillary craniopharyngioma, factor VII deficiency, and atrial fibrillation. Interventions: To prevent bleeding, a total of 8 doses of recombinant activated factor VII and 1 dose of fresh frozen plasma were administered as the perioperative replacement therapy. This scheme was guided by a pharmacodynamic evaluation, laboratory tests, and imaging examinations. Outcomes: No excessive surgical bleeding was observed during the 22-day treatment. The patient was found to have compound heterozygous mutations, Ala304Thr (c.910G > A) and IVS5-2A > G (c.572-2A > G), in the F7 gene. Lessons: This is the first reported case in which surgical hemorrhage secondary to brain tumor resection was successfully controlled in the presence of congenital factor VII deficiency. Perioperative coagulation state, hemostasis, and thrombosis events should be closely observed, and the interval and dosage of recombinant factor VIIa should be adjusted accordingly.


Introduction
[3] FVIID can cause spontaneous bleeding, including menorrhagia, ecchymosis, epistaxis, gum bleeding, hematuria, gastrointestinal bleeding, hemarthrosis, and intracranial hemorrhage. [4]Unlike hemophilia, factor VII activity (FVII:C) does not serve as a predictor of hemorrhage severity. [5]The primary therapeutic option is replacement therapy (RT), which includes recombinant activated factor VII (rFVIIa), fresh frozen plasma (FFP), plasma-derived factor VII, and prothrombin complex concentrates. [6]Furthermore, 40% to 70% of patients remain asymptomatic, [4,7,8] for whom surgery is considered a major threat. [9]Most of them are occasionally diagnosed by a prolonged prothrombin time (PT) and a decreased FVII:C in preoperative coagulation tests. [10]Despite the absence of previous bleeding episodes, the inherent hemostatic defect is consistently a predisposition to excessive bleeding.In patients with coagulation factor deficiency, the prevention of surgical bleeding should be meticulously considered. [11]However, effective guidelines for the perioperative coagulation management of patients with FVIID have yet to be established, and consensus on the optimal strategy for rFVIIa infusion remains elusive. [12]Currently, the perioperative management of patients with FVIID are individualized, considering factors such as hemorrhage history, family history, FVII:C baseline, and the specific type of surgery. [10]raniotomy is a significantly risky procedure compared to general surgical procedures.Whether it is for trauma, cerebrovascular disease, or tumor, intracranial hemorrhage is a common complication with considerable rates of disability and mortality.The prevention and management of perioperative intracranial hemorrhage are major concerns for neurosurgeons.However, cases of FVIID involving craniotomy for treatment of nonhemorrhagic disorder are insufficient in the available literature, and surgical treatment for brain tumor in patient with FVIID has not been reported.
In this report, we present an asymptomatic FVIID patient, who underwent a craniotomy for papillary craniopharyngioma resection.In addition, similar cases managed with rFVIIa were reviewed.This is the first report on perioperative management of brain tumor resection in patient with FVIID.This case serves an example that, repeated rFVIIa infusions can effectively prevent and control intracranial hemorrhage complicated by craniotomy for brain tumor resection.

Case presentation
A 55-year-old man suffered from recurrent headache, dizziness, and progressively blurred vision for over 2 months.To clarify diagnosis and treatment, he went to a local hospital for medical consultation.Magnetic resonance imaging revealed a space-occupying lesion in the sellar region.After examinations, he was diagnosed as benign tumor in the sellar region, along with optic nerve compression, factor VII deficiency, and atrial fibrillation.Considering the significant risk of craniotomy, the hospital recommended transferring him to a superior hospital.One week after his discharge, the patient came to our hospital for further treatment.
Upon admission, the patient denied personal and family history of spontaneous hemorrhage.The physical examination showed: body temperature 36.0°C,pulse rate 55 times/min, respiratory rate 20 times/min, blood pressure 105/81 mm Hg, body weight 74 kg.He was neurologically normal but complained of headache, dizziness, and vision decrease, and his heart rhythm was normal.A risk assessment of venous thromboembolism was conducted, which indicated low risk with a Caprini score of 1. Laboratory examination showed normal hepatic and renal function but an isolated prolonged PT of 43.60 seconds and a decreased FVII:C of 2.0% (Table 1).For full workup, computed tomography (CT), cerebral volume scanning, magnetic resonance imaging (1.5 T) plain scanning and enhanced scanning were performed.The imaging examination showed cystic masses in the suprasellar region and calcification lesions in the right basal ganglia area (Fig. 1A and B).Echocardiography showed enlargement of left and right atrium, moderate mitral regurgitation, and slight tricuspid valve regurgitation.
Subsequently, his case was further discussed at the multidisciplinary team (MDT) meeting, which included 7 neurosurgeons, a hematologist, an endocrinologist, a laboratory physician, and an anesthesiologist.The neurosurgeons suggest that the tumor growth would further compress the optic nerve, hypophysis, hypothalamus and cerebrospinal fluid circulation, and encompass the carotid artery, thereby leading to vision loss, hypopituitarism, and life-threatening hydrocephalus.
The hematologist and laboratory physician highlighted that, the patient had FVIID and atrial fibrillation for years, both of which simultaneously carried the risks of surgical bleeding and thrombosis.Despite the absence of bleeding phenotypes, the FVII:C levels should be maintained above 20% through preoperative RTs.Given these conditions, the MDT decided to offer him surgical treatment and preoperative coagulation correction along with intensive monitoring of coagulation function, hemorrhage, thrombosis and other potential complications.The patient and his family agreed to use rFVIIa for RT.
Preoperatively, the pharmacodynamics of rFVIIa was evaluated through hourly measurement of FVII:C levels, thromboelastograms, and PTs and international normalized ratio (INR) following an intravenous administration of 1.5 mg rFVIIa, equivalent to 20.3 μg/kg body weight (Fig. 2A and Table 2).At 9:18 am the next day, a craniotomy was performed for the excision of the tumor in the supersellar region.Thirty minutes before the surgery began, a dose of 1.0 mg rFVIIa, equivalent to 13.5 μg/kg, was given for the prophylaxis against intraoperative bleedings.Intraoperatively, upon opening the skull, the surface of dura bled and was treated with bipolar electrocoagulation.To prevent excessive bleeding, rFVIIa was used again at the same dosage.The tumor was resected incompletely due to the adhesion of the tumor capsule to the third ventricle and hypothalamus.The operation was successful and lasted for 347 minutes, with bleeding amount of approximately 300 mL.No red blood cell or plasma were infused.The tumor was diagnosed as papillary craniopharyngioma (World Health Organization Grade 1) by histopathology, supported by antigen staining and Periodic Acid-Schiff staining.
After the surgery, a risk assessment of venous thromboembolism was conducted, where the Caprini score is 6, indicating high risk.Cranial CT showed a small amount of bleeding in the surgical area (Fig. 1C).Consequently, 2 doses of rFVIIa (13.5 μg/kg) was used to prevent excessive postoperative bleeding.The following morning, the patient had regained consciousness from anesthesia.He reported pain at the surgical site, without any other significant discomfort.The intervals of FVII supplementation were extended, and the patient's coagulation function was monitored by daily measurements of PT and INR (Fig. 2B and Table 2).Three days after the surgery, the patient was found drowsy and slow to response.A CT scan showed a minor hematocele in the surgical region (Fig. 1D).The INR level had elevated to the baseline (Fig. 2B and Table 2).Consequently, 2 doses of rFVIIa (20.3 μg/kg) was given to him.Six days after the surgery, his consciousness had recovered well.The follow-up cranial CTs revealed that no new hemorrhage occurred, and the intracranial hematocele was resolved (Fig. 1D and E).Thrombosis in the heart and lower limb veins was ruled out by ultrasounds.After 12 days of postoperative observation, the patient recovered well, without hemorrhage, thrombosis or arrhythmia, and was discharged on the 22-nd day of hospitalization.

Review and discussion
Perioperative bleeding is a potential complication of surgical procedures, which is easily triggered in FVIID due to the presence of hemostatic defect. [9,13]Surgical bleeding is not uncommon in the setting of FVIID.Approximately 17% to 30% of cases will experience surgical bleeding, and the prevalence is about 8% in the asymptomatic cases. [7,14]An MDT discussion including hematologists is required for the surgical treatment of patients with FVIID. [13]RT is routinely used in the perioperative management of FVIID, with rFVIIa being the most commonly used (78%), followed by FFP (10%), plasma-derived factor VII concentrate (10%), and prothrombin complex concentrates (2%). [3]rFVIIa has been widely used in the United States and Europe.Generally, it is recommended to dose 15 to 30 μg/kg of rFVIIa every 4 to 6 hours until the surgical incision heals and hemostasis is achieved for patients with plasma FVII:C < 20% undergoing major surgery. [15,16]However, factors other than baseline FVII:C level may affect hemorrhagic outcomes.Spontaneous bleeding occurred previously has been shown to be significantly associated with surgical bleeding. [14]Therefore, it is important to individualize the dosage and interval of RTs for each patient.Sheth et al [12] proposed an algorithm for perioperative management, where a FVII:C threshold of 20% was used to distinguish risk of bleeding, while hemorrhage history, family history and whether to undergo major surgery were taken into account.The risk of surgical bleeding should be more conservatively evaluated in children.Benlakhal et al [14] suggested that for prepubertal patients with FVII:C levels of 10% to 30%, RT should be given regardless of whether they had a hemorrhage history, as they had almost never encountered the hemostasis challenge, which makes the negative hemorrhage history less reliable than that of adults.These aforementioned studies collectively reflected that personal and family hemorrhage history is important in predicting surgical bleeding.
The rFVIIa regimen for patients with FVIID have been evaluated in prospective observational studies.Mariani et al study suggested that a regimen of 3 doses, with the first dose exceeding 13 μg/kg on the operative day, is capable to effectively prevent bleeding during major surgery. [13]Another study by Di Minno et al revealed that a history of major bleeding, rather than plasma FVII levels, was the sole independent predictor of the number of RT doses and RT duration. [10]Interestingly, asymptomatic patients undergoing major surgery received RT at an average of moderate doses but for just 1 day, most likely limited to the operative day, which is remarkably less than the recommended scheme. [10]Similar low-dose rFVIIa RTs in the context of asymptomatic FVIID, major surgery and FVII:C < 5% were also described in some case reports.These include one case with only 2 doses at 15 μg/kg [17] and 3 cases with only single doses within 6 μg/kg. [18]Khazi et al also reported one patient who did not receive any RT. [19]However, several cases receiving remarkably more rFVIIa doses were also reported, [17,20,21] and these may represent unusual cases, suggesting that the dosage of rFVIIa may also be influenced by the type of surgery, clinical pre-thrombotic status, anticoagulant drugs, and the experience of clinical physicians (Table 3).Overall, patients with asymptomatic FVIID undergoing major surgery tend to receive lower dosage of rFVIIa than the recommended dosage, and perioperative management of unusual cases should be orchestrated under the thorough consideration of special surgical complications, thrombosis risk, and medication history.
Our patient had no history of hemorrhage or family history.He was scheduled for craniotomy, and his baseline FVII:C level was 2.0%.Bleeding in the surgical region might lead to a second craniotomy treatment, or even disability or mortality.Given these, the low doses of rFVIIa similar to the reports mentioned above are deem inappropriate for our case.While rFVIIa has been commonly used for hemostasis in neurosurgery in patients without FVIID, the regimen may not be suitable for neurosurgery in patients with FVIID. [26]Therefore, we opted to first evaluate the pharmacokinetics of 1.5 mg FVIIa (20.3 μg/kg), and subsequently adjusted the dosage of rFVIIa based on the evaluation result, administering it at the recommended intervals.Twenty-four hours after the surgery, we extended the intervals between administrations, regarding the high incidence of venous thrombosis in brain tumor surgery. [27]Doses were given only when PT and INR returned to the baselines, thereby preventing hypercoagulability (Table 2).Meanwhile, the atrial fibrillationrelated cardiac dysfunction and thrombosis were closely monitored.
[30] Importantly, FVIID is not a protective factor for postoperative thrombosis. [28]Factors that influence the risk of postoperative thrombosis in patients with FVIID include type of RT, prethrombotic status before surgery, and type of surgery. [31,32]The patient's craniopharyngioma had the potential to invade the hypothalamus and pituitary gland, which may result in complex postoperative complications involving electrolyte disturbance, endocrine disturbance, and subsequent hormone RT. [33,34] These factors could potentially increase the risk of venous thrombosis.Additionally, the patient had atrial fibrillation, known to increase the risk of thrombosis.His atrial fibrillation was asymptomatic and untreated for many years.The use of anticoagulants may lead to a failure of intracranial hemostasis.In view of  these considerations, we opted not to use anticoagulants and instead closely monitored the patient's cardiac function and potential thrombosis in the heart and lower limb venous.rFVIIa was chosen as the safest RT option.Although expensive, rFVIIa is regarded as the overall best RT option, [35] without introducing coagulation factors other than the defective, and is associated with effective hemostasis [36] and low risk of thrombosis. [28,32]The patient ultimately received a total of 8 doses of rFVIIa and 1 dose of FFP serving as the final dose at the end of postoperative recovery period.No other hemostatic drugs were used.
In conclusion, we presented a case of asymptomatic FVIID undergoing craniotomy for resection of brain tumor, where the hemostasis challenge was rare and stern in the context of asymptomatic FVIID.We suggest that in the case of asymptomatic patients undergoing surgical procedures with extremely high risk of bleeding, the individual pharmacodynamics of rFVIIa should be evaluated first.Furthermore, perioperative coagulation state, hemostasis and thrombosis events should be closely observed, and the interval and dosage of rFVIIa should be adjusted accordingly.These can effectively help prevent excessive surgical bleeding.The prevention of complicating venous thrombosis should also be noted after major surgery for patients with FVIID.An optimized strategy on perioperative management for such patients requires experience from more case studies and reports.†Values given as median (range).‡Values were estimated since the exact data was not available.

Figure 1 .
Figure 1.Cerebral CT and MRI results of the patient.(A) Cranial MRI and (B) CT showed cystic masses in the super sellar region.(C) Cranial CT showed scattered small patchy hematocele in the surgical area 6 hours after the surgery.(D) The density of hematocele decreased 3 days after the surgery.(E) Intracranial hematocele was resolved 6 days after the surgery.CT = computed tomography, MRI = magnetic resonance imaging.

Figure 2 .
Figure 2. Dynamics changes of coagulation function test results.(A) Plasma FVII activity and international normalized ratio within 4 hours after the first dose.(B) International normalized ratio.Time axis starts from 0:00 am on the 8th hospitalization day.

Table 1
Laboratory tests results of the patient before treatment.

Table 3
Replacement therapy with rFVIIa on preoperative days/operative day/postoperative days in asymptomatic patients who underwent major surgery.